Bipolar disorder (BP) characterized by a dysregulation of mood, impulsivity, risky behavior, and interpersonal problems, is a recurrent and often chronic psychiatric illness. According to the World Health Organization (WHO), BP is the sixth leading cause of disability-adjusted life years worldwide among persons aged 15 to 44 years. It is associated with functional impairment, elevated suicide rates, and utilization of mental health systems.
BP is known for recurrent depressive, manic, and mixed episodes, and BP is divided into several categories. However, BP is commonly under-recognized, even in psychiatric settings. Increasing evidences suggest that neuronal degeneration may relate to the etiology and progression of bipolar disorder. Imaging studies suggest that ongoing neuronal atrophy accompanies the disorder. For instance, PET images of the cerebral blood flow and the rate of glucose metabolism, both indicative of brain activity, detect a reduced activity in the subgenual prefrontal cortex during the bipolar depression. This decrement in activity in part corresponds to a reduction of cortical volume, similar in a manner to that seen in magnetic resonance imaging demonstrating the reduced mean volume on grey matters. In BP, abnormalities of the third ventricle, frontal lobe, cerebellum, and possibly the temporal lobe are also noted. These observations suggest a neuronal dysfunction and possibly neuronal loss may be involved in the pathogenesis of BP. Therefore, BP may represent a neuro-degeneration disease.
In addition, BP may be associated with induction of a lot of endotoxins and exotoxins which may increase neurotoxins as well as decrease of neurotrophic factors duo to overactivate microglial cell and inhibit astroglia cell. Those effects may induce pre-inflammatory factors such as TNF-α, C-reactive protein, interleukins, etc. and decrease BDNF etc. which will cause neuron damage or necrosis. The vicious cycle will lead to progressive worsening of the disease.
While the pharmacological guidelines for treatment are well established, treatment for BP remains less than ideal. Most individuals still have breakthrough episodes or significant residual symptoms while on medication. In addition, functional deficits often remain even when patients are in remission. Moreover, most BP patients are newly diagnosed who have not taken any mood stabilizer or antipsychotics in the past. Because many patients with BP remain symptomatic even when fully adherent to their medication regimens, greater understanding of the pathogenesis of this illness and novel treatment modality other than current regimen of mood stabilizers and antipsychotics is needed.
Cholesterol is an organic molecule. It is a lipid molecule and is biosynthesized by all animal cells because it is an essential structural component of all animal (not plant or bacterial) cell membranes that is required to maintain both membrane structural integrity and fluidity. Cholesterol travels through bloodstream in small packages called lipoproteins. These packages are made of fat (lipid) on the inside and proteins on the outside. Two kinds of lipoproteins carry cholesterol throughout body: low-density lipoproteins (LDL) and high-density lipoproteins (HDL). Having healthy levels of both types of lipoproteins is important. LDL cholesterol sometimes is called “bad” cholesterol. A high LDL level leads to a buildup of cholesterol in arteries. HDL cholesterol sometimes is called “good” cholesterol. This is because it carries cholesterol from other parts of body back to liver, so that liver can remove the cholesterol from body. High cholesterol level increases the risk of some conditions, such as coronary heart disease, stroke, peripheral vascular disease, type 2 diabetes, and high blood pressure. Therefore, a method for decreasing cholesterol or LDL level in body is needed.
Dextromethorphan (DM) has been used as an antitussive drug with little side effect for more than 50 years in clinics. It is known to have a wide margin of safety. DM has been shown to be neuroprotective in rodents and protects the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- or lipopolysaccharide (LPS)-induced dopaminergic neuronal damage in vitro and in vivo. Furthermore, DM also protects against the ischemia-induced neuronal damage in rats and has been reported to have neuroprotective effect on monoamine neurons and to have protective effect against endotoxicity and extratoxicity. DM has neuronal protective effects in high dose and low dose. However, the high dosage of DM may cause side effects including body rash/itching, nausea, vomiting, drowsiness, dizziness, constipation, sedation, confusion, nervousness, and closed-eye hallucination. The high dosage of DM may not only increase side effect but also confuse the detailed mechanism of medication; the low dosage will demonstrate the specific effect of the DM in the decrease of cytokine including TNF-α and neuroprotective effect. The mechanism of the neuroprotective effects of low dose DM is associated with the inhibition of microglia activation but not with its N-methyl-D-aspartate (NMDA) receptor antagonist property. Moreover, a better correlation is found between the anti-inflammatory potency and the neuroprotection of low dose DM. These results suggest that the neuroprotection provided by low dose DM in the inflammation-related neurodegenerative models is not mediated through the NMDA receptor. U.S. Pat. No. 8,785,472 (Publication No. 2011/0281904 A1) suggests that DM is effective in the treatment of BP patients. In addition, low plasma levels of DM (5-100 ng/ml) found in these patients suggests that this beneficial effect of low dose DM is not mediated through the blockade of NMDA receptors. The clinical studies have indicated that patients taking 30-60 mg/70 kg of DM showed plasma DM concentrations of about 10-30 ng/ml (28-84 nM) which is not effect in NMDA receptor. The same low dose of DM causes a significant anti-inflammatory as well as a BDNF-increasing effect in bipolar disorder patients.
Memantine used to be recognized as a noncompetitive N-methyl-D-aspartate receptor antagonist. It was found to have neuroprotective effect in several neurodegenerative diseases in the past years. Memantine can inhibit brain inflammatory response through its action on neuroglial cells and provide neurotrophic effect. Mechanistic studies reveal that the high potency of small dosage of memantine is due to its dual actions: an anti-inflammatory effect by reducing the activity of microglia and an increase in the release of neurotrophic factors, such as BDNF, GDNF by astroglia (U.S. patent application Ser. No. 12/486,630 (Publication No. 2009/0253803 A1). It is also found that even 1/100 dosage of memantine (0.2 mg/kg) may be effective in opioid addictive behavior in rat by conditioned place preference.